Cyclic Olefin Copolymer (COC) in the pharmaceutical industry

Rochester Institute of Technology Rochester Institute of Technology

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Cyclic Olefin Copolymer (COC) in the pharmaceutical industry Cyclic Olefin Copolymer (COC) in the pharmaceutical industry

Amgad Khalil

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Cyclic Olefin Copolymer (COC) in the Pharmaceutical Industry

by

Amgad Khalil

A Thesis Project

Submitted to the

Department of Packaging Science

College ofApplied Science and Technology

In partial fulfillment of the requirements for the degree of

Master of Science

Rochester Institute of Technology

2004

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Department of Packaging Science College of Applied Science and Technology

Rochester Institute of Technology Rochester, New York

CERTIFICATE OF APPRO V AL

M. S. DEGREE THESIS PROJECT

The M.S. degree thesis project of Amgad Khalil has been examined and approved

by the thesis committee as satisfactory for the requirements for the Master of Science Degree

Deanna M. Jacobs

Deanna M. Jacobs RIT, Packaging Science Graduate Program Chair

III

Craig E. Densmore

Craig E. Densmore RIT, Packaging Science Professor and

Agrilink Director Packaging Procurement

Daniel L. Goodwin

Daniel L. Goodwin, PhD RIT, Packaging Science Professor

August 2004

COPY RELEASE

Permission From Author Required

CYCLIC OLEFIN COPOLYMER (COC) IN THE PHARMACEUTICAL INDUSTRY

I, Amgad Khalil, prefer to be contacted eac h lime a req uest for reproduction is made. If permission is granted, any reproduction will not be for commercia l use or profit. I can be reached at the fo llowing address:

Amgad Khalil

Date: March 21, 2005 Signature of Author: Am gad Kh a Ii I

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ACKNOWLEDGEMENTS

I would like to thank my advisors- DeannaM. Jacobs, Craig E. Densmore and Dr. Daniel L.

Goodwin from Rochester Institute ofTechnology- for their guidance and support.

DEDICATION

I dedicate this thesis to my wife Suzy, my son Jeremy, and my daughter Justine, as well asto my

brother Aiman and mother Alice. It is their love and support that helped me navigate through my

educational journey.

My wife's unending belief in me and unmatched sacrifice; my children's love, hugs, and kisses;

my brother as a role model; and my mother's encouragement are whatkept me going.

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ABSTRACT

The purpose of this research was to evaluate an alternative to polyvinyl chloride based

packaging materials for pharmaceutical blister packaging that is neither harmful to the

environment nor corrosive to the equipment used in pharmaceutical packaging. Olefin structures

(PP/COC/PP) were tested and compared to halogen based material (PVC/PVDC) using the

following criteria:

Moisture Vapor Transmission Rate (MVTR)

Vacuum leak test

Peel strength test

Machine ability and form-ability on an Uhlmann UPS4 thermoformer

Layer distribution

Financial impact

Cyclic Olefin Copolymers (COC) was proven to have the properties required to

adequately protect the product while being environmentally safer than PVDC and CTFE.

vn

TABLE OF CONTENTS

BACKGROUND 1

PVC (POLYVINYL CHLORIDE, VINYL) 3

PVC Toxicity 5

Transport Nightmare 7

Packaging ShelfLife 8

Is PVC Recyclable? 8

PVC Disposal 9

PVC Illusion 11

Victims of the PVC Industry 12

AN ALTERNATIVE TO PVC FOR PHARMACEUTICAL PACKAGING 14

COC (OLEFIN POLYMER) 15

Development and Structure ofCOC 15

Manufacturing ofCOC 15

COC in Flexible Films 16

Environmentally SafeBlister Packagingwith ImprovedBarrier Properties 17

Processing 18

Properties of COC 18

PharmaceuticalBlister PackagingRequirements 19

TEST RESULTS 20

MVTR 21

VacuumLeakTest 30

Peal StrengthTest 31

OpticalLayerGauge 33

Price Comparison 37

CONCLUSION 38

CONSIDERATIONS 39

REFERENCES 40

APPENDIX A: DEFINITIONS 42

vm

LIST OF FIGURES

Figure 1. Uhlmann Thermoformer, Model # UPS4 MT (Pfizer Parsippany Plant) 22

Figure 2. MVTR Data Graph 29

Figure 3. Blister Vacuum Leak Tester (Pfizer Parsippany Plant) 30

Figure 4. Blister Peal Strength Tester (Pfizer Parsippany Plant) 31

Figure 5. Peal Strength Graph 32

Figure 6. The Davinor Layer Gauge 33

Figure 7. Material Distribution Graph 36

Figure 8. Price Comparison Graph 37

LIST OF TABLES

Table 1. Packaging Thermoformer Equipment Setting 23

Table 2. 120 Micron MVTR Test Summary 24



Table 5. 300Micron MVTR Test Summary 27

Table 6. PVC/PVDC MVTR Test Summary 28

Table 7. MVTR Data Summary 29

Table 8. Vacuum Leak Summary 31

Table 9. Peal Strength Summary 32

Table 10. Optical Layer Gage Summary 34

Table 11. Price Comparison 37

IX

BACKGROUND

Although Regnault prepared some vinyl and/or vinylidene monomers in 1838, and

observed the conversion of the latter to a white powder when exposed to sunlight in sealed tubes,

it is Baumann's polymerization of vinyl chloride (as well as bromide) in 1872 that is often

regarded as the earliest documented preparation of PVC homopolymer (Titow, 1984). But in the

USA, Bakelite was the first truly synthetic polymer discovered and was safer and tougher than

any previously discovered chemically modified variants of natural polymers. Bakelite

(Thermoset) was made from phenol and formaldehyde and had suitable properties to make it an

ideal plastic for electrical appliances. However this plastic had room for improvement, which led

to the discovery and production ofmany more synthetic plastics in the years between the two

WorldWars. Hermann Staudinger, a German chemist, won the 1953 Nobel Prize for Chemistry

for demonstrating that polymers were built from smaller units that had joined together to form

long chains of molecules (Encyclopedia Britannica, 2004). His work laid the foundation for the

great expansion of the thermoplastic industry later in the 20th century.

By the end of the 1930s, commercial production of synthetic polymers was on the rise.

For example, nylon was discovered in the mid 1930's by the chemistWallace Carothers who

worked for the Dupont research laboratory (About, 2004). Nylon was used to make clothing

material and was considered a luxurious novelty. Another discovery was polyvinylchloride

(PVC), which was first produced commercially in the USA in 1933, had an important use as

cable insulation during World War II, and soon after was used for many more applications

(Seymour, 1982).

Polyvinylchloride (PVC) [-(-CH2 -CHCl-)n-] is one of the three most widely used

polymers in the world. This is because PVC is one of the cheapest polymers to make and has a

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large range of properties that can be used to make hundreds of products. PVC is formed by the

polymerization of vinyl chloride (chloroethane) monomer units. It consists of polar molecules

that are attracted to each other by dipole-dipole interactions due to the electrostatic attractions of

a chlorine atom in one molecule to a hydrogen atom in another atom. These considerable

intermolecular attractions between polymer chains make PVC a fairly strong material.

Uncompounded PVC is colorless and rigid and possesses poor stability towards heat and light.

However, the use of additives and/or stabilizers enables changes the properties of the PVC so it

can be used for countless different applications (Titow, 1984).

During the 1930's, large amounts of chlorine became available in Nazi Germany as a

consequence of a program meant to make Germany independent of imported cotton in case of

war. This program concentrated on the production of rayon, and to this end large amounts of

caustic soda from the chlor-alkali industry were needed. After years of experimenting with

stabilizers, lubricants, and softeners, it was found that fibers could be made from PVC; these had

the added bonus of using up the excess chlorine produced by the expanded chlor-alkali industry.

What had previously been a toxic waste by-product of caustic soda manufacturing, became a

marketable commodity (Greenpeace Austria, 1991).

But the 1970's brought two unforeseen events, both with a major impact and lasting

effects: (1) the oil crisis of 1973/1974, which contributed to the rise of oil prices, and (2) the

discovery that vinyl chloride monomer (VCM) is a carcinogen (Titow, 1984). The oil crisis

caused a serious temporary shortage of oil derivatives, which are an important feedstock for the

production of VCM. This drove the industry to turn to the by-product (waste) of caustic soda to

get the chlorine and hydrogen needed for the HC1.

PVC (POLYVINYL CHLORIDE, VINYL)

PVC is one of the most versatile of the plastic materials; it is also the most dangerous.

PVC is used in packaging such as mineral water bottles, tubs, boxes, cling film, food, and

pharmaceutical packaging. PVC plastic causes greater environmental concern than any other

plastic because the manufacture of PVC is linked to the production of chlorine to an

astronomical degree. Chlorine is a waste byproduct that originates from caustic soda production,

and it is a highly reactive chemical that must be combined with other materials (stabilizers).

Although chlorine compounds are found in nature (the obvious example is sodium chloride, or

common table salt), chlorine manufactured by the chlor-alkali process is quite different. This

chlorine gas is highly reactive; it must therefore be combined with organic compounds (material

containing carbon), and creates organochlorines.

In just a few decades, the chemical industry has distributed millions of tons of

organochlorines per year into our environment. The whole process represents an environmental

disaster. Some of the organochlorines associated with environmental and human health scandals

are familiar names:

Polychlorinated Biphenyls (PCBs), found to stop the reproductive ability of wildlife,

were banned in the late 1970's, although most of the millions of tons produced are

still circulating in the environment (Environment Safety and Health Manual, 2004).

Halons, Chlorofluorocarbon (CFCs), and Carbon Tetrachloride (CC14) will continue

to destroy the ozone layer into the next century even with an immediate ban on their

production (Ozone Depletion Glossary, 2004).

Pesticides - such as Dichloro-diphenyl-trichloroethane (DDT) and Lindane

(Hexachlorocyclohexne-HCH) or commonly known as benzene hexachloride-

are

still being produced.

Organochlorines are found in materials such as PVC as a form of dioxin, which is

known to promote cancer, reduce the efficacy of the immune system, and contribute

to miscarriages and birth deformity. It has been associated with the chemical

industry's worst chemical disasters in Seveso (an air leak disaster in Italy) and Love

Canal (waste dumping in Niagara Falls, NY). Because it literally changes the

functioning of human cells, the effects can be very obvious or very subtle. Because it

changes gene functions, it can cause so-called genetic diseases to appear, and can

interfere with child development. There is no"threshold"

dose - the tiniest amount

can cause damage, and the human body has no defense against it.

PVC creates environmental problems throughout its life cycle. The production of PVC

powder involves the transport of dangerous explosive materials and the creation of toxic wastes.

Then, because PVC on its own is almost useless as a plastic, it must be combined with a number

of chemical additives to make it soft and pliable, heavy metals to make it hard or give it color,

and fungicides to stop bacteria from eating it. Thus, PVC production also gives rise to a huge

secondary and toxic manufacturing industry. The product itself, when bought by the consumer,

can be immediately dangerous. For instance, certain additives, such as those used in flooring,

will evaporate into the air. The most common plasticizer additive is a suspected carcinogen. The

disposal of PVC creates further environmental problems. When burned, it releases an acidic gas,

as well as toxic dioxins and other organochlorines because of its chlorine content; when land

filled; it leaches into the ground and threatens the groundwater supplies. PVC is not a natural

material and will therefore not biodegrade, a feature that the PVC industry is in fact proud of

(Clayton, 1991).

The PVC industry is trying to set up recycling plans, but the range of PVC products

makes it impossible to recycle, since each PVC product contains many different additives. The

industry admits that recycling is expensive and of value primarily from the point of view of

public relations. Meanwhile, our world is filling up with PVC products and the industry is

expanding into Latin America and Asia. PVChas always been a low-price product; after all, it

originated as a method of disposing of industrial waste, and this price advantage is the key to its

success.

PVC Toxicity

PVC is considered by its proponents, such as Norsk Hydro, as an extremely resource

efficient plastic with low energy consumption; nearly 60% of its composition is based on

common table salt, a product available in almost unlimited quantities. What this statement does

not reveal is that in the course of PVC production, common table salt is turned into chlorine gas

and organochlorines, one of the most dangerous group of chemicals ever synthesized. It is this

use of chlorine that distinguishes PVC from other plastics and makes it so dangerous.

The discovery in the 1970's that exposure to VCM could cause certain types of cancer

and other irreversible health hazards affected PVC production for many years. Chlorine and

ethylene are combined to make ethylene dichloride (EDC); the EDC is then used to make VCM.

EDC is highly toxic and easily absorbed through the skin. It causes cancer andbirth defects;

damages the liver, kidneys, and other organs; and can cause internal hemorrhaging and blood

clots. It is also highly flammable: the vapor can explode, generatinghydrogen chloride and

phosgene, two highly toxic gases that can cause Bhopal-typeaccidents. It is impossible to

produce organochlorines without wastes or residues andin the case of PVC production many of

these residues, or tars, used to be incinerated at sea.

The main hazard areas may be collectivelyidentified as the risk of harmful effects on

contact with the PVC materials themselves, or their individual constituents, or decomposition

products, during any of the phases of thematerials'

life history. The principal possible harmful

effects are poisoning, carcinogenic action,irritation or tissue damage, and dermatitis. The form

of contact through which they can arise are ingestion, inhalation,absorption or simply

prolonged/repeated external contact (Titow, 1984). In the US, a legal action for $285 million

dollars was brought by some supermarkets against Borden Chemical Corporation and Goodyear

Tire and Rubber Co. (two PVC polymers producers) based on damage to health attributed PVC

film used to wrap meat (Titow, 1984).

Thermal decomposition of PVC is permitted to occur in a controlled processing area, but

when in accidental fire or as a means of disposal (incinerations), toxic fumes are produced.

These fumes contain considerable proportions of hydrogen chloride (hydrochloric) and hydrogen

fluoride (hydrofluoric) acids. These appear as white fumes, which are highly irritant.

Following the global ban on ocean dumping and ocean incineration agreed to in the early

1990's by the Basel and Bamako convention, PVC residues and wastes are either incinerated

(generating the same type of toxic emissions), sent to landfills, or injected into deep wells.

However, not all waste residues are incinerated, vented, or dumped. Through a process called

chlorolysis, approximately a third of these residues are turned into new chlorinated products.

Many are familiar: the chlorinated solvent perchlorethylene is the common dry cleaning fluid

and a suspected carcinogen; carbon tetrachloride is an ozone-depleting chemical and a known

human carcinogen. Other uses of chemical by products include pesticides, CFCs, cleaning fluids,

and the fragrance used in toilet products and for coffins.

As is true of all chlorine-containing products, these new applications spread more toxic

emissions into the air, soil, and water. Through the use of unnecessary toilet disinfections,

organochlorines have for years been washed into the sewer system. The use of similar products

in coffins causes highly toxic emissions such as dioxins from crematoria.

The VCM made from EDC is an extremely toxic, flammable, explosive and carcinogenic

gas. Symptoms of VCM poisoning include softening of bones, deformation of fingers, skin

complaints, impotence, bad circulation and shortness of breath, liver damage and even a special

form of liver cancer, angiosarcoma. Strict standards have consequently been set in many

countries to limit worker exposure, as well as the amount of un-polymerized VCM allowed to

remain in finished products, although these standards may not exist in foreign factories or their

products. However, standards can never solve the problem. VCM is impossible to contain within

a plant no matter how tight the system. The reality is that the chemicals used to produce PVCare

toxic; it is impossible to contain all these chemicals during manufacture no matter how

sophisticated and well monitored the plant is; and the risk of spills, accidents, and bad on-site

management only intensifies the problem.

The first limits recommended in the United Kingdom (in the mid-1970s) for a maximum

VCM concentration in factory atmosphere started with a time weighted average figure of 25 ppm

(by volume), soon to be reduced to 10 ppm with further provision that whenever possible zero

concentration should be aimed at (UK Health and Safety Executive, 1975). In the meantime, the

US Food and Drug Administration limited VCM concentrations to lppm and prohibited the use

of rigid and semi-rigid PVC for food packaging applications (bottles, film etc.) unless it could

shown that no migration of VCM into the content would occur. Through extensive research and

testing, the levels of VCM were reduced to undetectable levels in the unplasticised PVC. But the

fact remains that only complete avoidance of exposure toVCM can entirely eliminate the risk.

Transport Nightmare

In view of the nature of VCM, it is extremely disturbing that most of the vast quantity of

VCM produced worldwide is manufactured far from where it will be eventually polymerized into

PVC. It is therefore transported around the world from industrial plant to industrial plant, by

road, rail, and sea.

The risk of accidents represents dangers to communities living along these transport

routes. When transported, VCM is compressed and liquefied. Any leaks can lead to explosions,

since ignition temperatures and critical temperatures are both low (minus 77 and below 160

degrees Celsius, respectively). When VCM escapes, it forms pools of mist which, being heavier

than air, creep along the ground. If ignited, they will flash back to the source of leakage. Large

VCM fires are almost impossible to contain. VCM is only slightly soluble in water and reverts to

a gaseous state quickly, floating above the water until it forms a gas. On the water surface, it

combines with air to form explosive mixtures. VCM leaked into sewage systems is also highly

explosive. Serious rail transport accidents involving VCM are well documented; at least 17 took

place between 1964 and 1980.

Packaging ShelfLife

Packaging shelf life is divided between long shelf life and short shelf life. Products that

are packaged with a short shelf life-

typically two years or less before they are thrown away-

are usually small in size. Examples of products with short shelf life include pharmaceutical

products, medical supplies, and office supplies. PVC is a major packaging material for these

short shelf life packages. All the problems associated with PVC also apply to PVDC and CTFE,

another chlorinated plastic widely used in packaging. An inherent characteristic of packaging

with a short lifespan is that once it has served the purposes of display, containment, and

protection, it becomes waste- light but voluminous.

Is PVCRecyclable?

A major goal set by the PVC industry to improve its image is to create the impression

that PVC is an environmentally acceptable material, one that can be recycled. The US plastics

industry has noted that the image of plastics among consumers is deteriorating at an alarmingly

fast pace. In response to this increased public awareness, the plastics industry launched two

major public relations efforts. The first was to demonstrate the biodegradability of plastics,

which failed miserably. Their second effort has been more successful. Their strategy has been to

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build on society's positive response to recycling while increasing PVC's market share and

avoiding any attempt to legislate product bans or restrictions. In reality, post-consumer plastics

recycling is negligible, despite the fact that the PVC industry feels itself under intense pressure to

prove the recyclability of chlorine containing plastic. That pressure has been increased by the

fact that Denmark, Sweden, Switzerland, Germany, and Austria have placed restrictions on PVC

packaging owing to the incineration problems it presents.

PVC belongs to the family of plastics known as thermoplastics. These plastics, which

include polyethylene, polypropylene and polystyrene, can be remelted and reformed, in contrast

with the thermosets such as polyurethane, which cannot be re-melted or reformed. PVC can

therefore theoretically be recycled, and reprocessing of scrap during production routinely takes

place, usually in the interests of production economics rather than of environmental protection.

Genuine recycling, however, is post consumer, which takes place with products that have already

completed a useful life. Attempts to recycle these post consumer PVC plastics are fraught with

problems.

PVCDisposal

Dealing with PVC waste involves special considerations such as selective reclamation

(e.g., separation from waste mixture with other plastics), which is not a simple task because of

the many additives that are contained in the variant of PVC material. Reprocessing is just as

complicated because of the side variety of the PVC formulations and the increased susceptibility

to heat degradation in re-processing (Titow, 1984).

One statement can be made with absolute certainty: PVC products will end up as waste.

This is not only because of the nature of the productsmade from PVC products, many of which

are cheap, mass produced consumer goods that have a short life and cannot be repaired, but also

because of the many formulations and additivespresent in different PVC products make them

impossible to recycle in the true sense of the word. Even the few products that are made from

post consumer PVC discarded products will sooner or later end up in the trash-

usually sooner.

Currently, millions of tons of PVC products are disposed of by incineration or landfill,

the costs of which are borne by the general public both in economic and human health terms.

Tests have shown that toxic stabilizers (barium/cadmium) can be leached from plasticized PVC

under landfill conditions. Plants can absorb these heavy metals, and products containing them

should not be disposed of in normal landfills. Even in a well-managed landfill, the composition

of the leachate (the liquid seeping through the body of the landfill) is unpredictable, varying with

the nature of the land filled waste, the amount of rainfall, the temperature, and a host of other

factors. The increasing volume of PVC being land filled, and the fact that not even the best

landfill membranes can prevent leachate escaping into the outside environment, set the scene for

future pollution of aquifers supplying drinking water.

Many countries incinerate a large proportion of their municipal solid waste, sometimes

with energy recovery. The chemical industry supports this method of waste management and has

coined the term "whitecoal"

to validate the use of waste plastics as a fuel. But the chlorine

content of PVC makes it completely unsuitable for incineration. Whenever chlorine is burned,

HCI (hydrogen chloride) is formed. This poisonous, corrosive substance must be removed from

flue gases to avoid serious environmental pollution, and this entails high capital investment,

efficient monitoring, and sizeable amounts of energy. Also, incinerators are easily damaged by

the corrosion that is generated by hydrogen chloride. It was for this reason in fact that the

chlorine and PVC industry created ocean incineration since the emissions were not captured by

scrubbers but spewed onto the ocean surface.

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PVC is also one of the greatest sources of dioxins and other organochlorines. The

incineration of a kilogram of PVC produces up to 50 micrograms of dioxin (TEQ), enough to

initiate cancer in 50,000 laboratory animals. Recent evidence of dioxin's toxicity details

reproductive problems in offspring of parents contaminated with low levels of dioxins. Hormone

changes and both demasculinization and defeminization of both sexes are now occurring in

wildlife populations. Incineration also produces toxic ash that must be disposed of in landfills. In

the case of PVC, for every 1 ton of PVC burned, 0.9 tons of waste salts are created. Because

these are contaminated with heavy metals or whatever additives there were in the PVC products

the salt must be disposed of. The costs of such emission cleaning and disposal are actually higher

than the cost of the new PVC product.

Finally, the PVC industry, well aware of the negative public image of their product, has

evolved an intriguing public relations concept: the "closed chlorinecycle."

Briefly, the acidic gas

from the incinerator is neutralized using large quantities of caustic soda to produce salt. This, the

industry maintains, is then re-introduced into the process to produce more chlorine and hence

PVC. In reality this only perpetuates MORE production of chlorine, rather than closing the cycle

because the production of caustic soda entails the production of almost equal amounts of

chlorine. Also the salts that are created after neutralization are usually contaminated with heavy

metals and other additives contained in the various PVC products thereby preventing their re-use.

It is obvious that the only solution for closing the PVC cycle is not to produce the product in the

first place.

PVC Illusion

The PVC industry advocates that its product is vital to modern society, and points to the

fact that PVC is used widely almost everywhere.This development is not due to the superior

qualities of PVC, but rather to the fact that it can price undercut many traditional materials such

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as wood, metals, or glass. However, if costs as a whole are considered, rather than merely the

purchase price of a PVC product, traditional materials will be seen to be more economical in the

long-term. Forward-looking companies, local authorities, and institutions have been becoming

increasingly aware of the threats posed by PVC and many have taken action.

The dangers posed by PVC products are now understood. The PVC industry, recognizing

that market saturation has been achieved in Western Europe and North America, is now planning

to expand to the newly- and less- industrialized countries. It is now paramount that this toxic

industry must not expand and that PVC bans and phase-outs must become an urgent priority for

both hemispheres.

Victims ofthe PVC Industry

Here are two vivid examples of victims of the PVC industry.

Fresh out of the Air Force, Dan Ross went to work for a Conoco vinyl chloride-producing

plant in Lake Charles, Louisiana in 1967. Dan's widow, Elaine, fell in love at first sight, and

after being married to him for 25 years, she says he could walk into a room and still take her

breath away. But his job was taking his breath away.

Elaine recalls, he came home from work one day, and he was taking off his boots and

socks, and I looked at his feet. The whole top of them were burned where the chemicals

had gone through his boots. I said, "My God, what was it that goes through leather,steel-

toed boots and your socks to dothat?"

As the years went by you could see it on his face. He started to get this hollow look under

his eyes, and I could always smell the chemicals on him. I could even smell it on his

breath after a while. But even up until he was diagnosed the first time, he said, "They'll

take care of me. They're my friends."(PBS.org, 2004)

In 1989, Dan Ross was diagnosed with a rare form of brain cancer, and 10 years after

Dan's death and a million pages of industry documents uncovered that exposure to PVC was the

ultimate cause.

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Bernard Skaggs landed a job with the BF Goodrich plant in Louisville, Kentucky, in

1955. The factory mixed vinyl chloride gas into a gooey dough that was then dried and processed

into pellets for PVC plastic. When Bernie Skaggs started having problems with his hands, he

first went to the company doctor-

who assured him the condition was not related to his work.

"My hands began to get sore, and they began to swell some. My fingers got so sore on the

ends, I couldn't button a shirt, couldn't dial a phone. And I had thick skin like it was

burned all over the back ofmy hand, back ofmy fingers, all the way up under my arm,almost to my arm pit. And after enough time, I got like thick places on my face, right

under myeyes."

(PBS.org, 2004)

Bernie's hands were eventually x-rayed. He was shocked looking at x-rays that showed

the bones in his fingertips had disappeared; his bones were being destroyed. The condition is

called acroosteolysis.

Thousands of other lives have been destroyed due to the silent killer (PVC). No one today

can avoid synthetic chemicals, but there are steps that people can take. The way to reduce the

dioxin threat is to stop burning trash and to stop producing PVC and other chlorinated chemicals.

If your town sends its trash to an incinerator, tell your town officials to institute comprehensive

recycling. Write to companies that use vinyl and ask them to use the known safe substitutes. Ask

your supermarket and office supply stores to sell Totally Chlorine Free (TCF) products. Learn

more about the dioxin threat. Read the books Dying From Dioxin by Lois Gibbs, and Our Stolen

Future by Theo Colborn. Talk to your friends and neighbors about dioxin and what you can do to

reduce the threat. "The Right-to-Know"

laws have made it possible for citizens to identify

specific companies and/or products that release the most toxic chemicals identified by the EPA.

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AN ALTERNATIVE TO PVC FOR PHARMACEUTICAL PACKAGING

An alternate material to polyvinylchloride (PVC) based materials that is not harmful to

the environment and not corrosive to the equipment is currently available for use in the

pharmaceutical industry. Cyclic Olefin Copolymers (COC) has the properties to protect the

product while it is environmentally safer than PVC.

As pharmaceutical manufacturers adopt blister packaging at a breathtaking rate, newer,

environmentally friendly, more efficient plastic materials are available to keep up with

performance demand. A pharmaceutical packaging market study revealed that currently

traditional plastic bottles (i.e., High Density Polyethylene (HDPE)) with closures retain a

considerable market share 30% - 35%, and the unit dose packages (blisters) make up 20% 25%

(CMS Info., 2004). The blister packaging market share will expand based on the anticipated

adoption of new FDA regulations requiring unit dose containers for institutional drugs, and will

generate above average growth opportunities and remain the leading type of pharmaceutical

packaging in value terms (Mindbranch.com, 2004).

Most new drugs are extremely hydroscopic; therefore, the pharmaceutical industry has

high standards for material performance. Water vapor transmission rate (WVTR), odor

permeation, impact protection, clarity, and formability are some of the characteristics that a

product must be tested against before the material is approved for pharmaceutical packaging. The

pharmaceutical industry has favored monolayer polyvinyl chloride (PVC), two layer coated

polyvinylidene chloride (PVDC), polypropylene (PP,) and chlorotrifluoroethylene (CTFE) with

base material Aclar. Most of the widely used plastics in the pharmaceutical industry give off

hydrochloric and hydrofluoric acids when heated and incinerated. Regulations in Europe and

Asia are discouraging the use of these materials for packaging purposes. Environmentally

14

friendly olefin plastics like Cyclic Olefin Copolymers provide long-term protection from

moisture comparable to that of PVDC and CTFE. And with its low density, it yields more film

per pound of resin.

COC (OLEFIN POLYMER)

The original patent of Eleuterio in 1957 reported the ring-opening polymerization of

cyclopentene, norbornene, etc. was the grounding breaking for a new family of Olefins (H. S.

Eleuterio, 1957). Cyclic Olefin copolymers, COC, are an interesting group ofmaterials that have

received increasing attention of late. These newly commercialized materials bring to the

marketplace a unique combination of properties that can be utilized in package development.

Development and Structure ofCOC

Cyclic Olefin copolymers are not new compositions ofmatter, having been known for

almost half a century. Particularly relevant are the efforts at the Leuna, near Leipzig in the

former East Germany, to copolymerize ethylene and norbornene over 30 years ago. Later, Mitsui

Petrochemical in Japan started to work on copolymers of ethylene and another cyclic olefin.

Both this work and that at Leuna were based on Ziegler/Natta type catalysts (Imamolgu, 1990).

Polymers based on this catalyst technology are more limited in product range, economics, and

purity than those based on metallocene catalysis. In the 1980's concentrated development of

COCs prepared via metallocene catalysis was undertaken (Draguta, 1985).

Manufacturing ofCOC

COC consists of an olefin copolymerized with a cyclic olefin. There are several COCs

available, produced by conventional addition polymerization. They are based on different cyclic

olefins. In the case of Topas COC, norbornene is the Cyclic Olefin used. Norbornene is produced

15

by the Diels-Alder addition of ethylene to cyclopentadiene. This is then reacted with ethylene in

the presence of a metallocene catalyst to form COC.

COCs are actually a family of polymers differentiated mainly by the heat resistance of the

materials. These polymers are all completely amorphous, statistically random copolymers with

no measurable degree of crystallinity. This is the result of the chain stiffening effect and bulky

nature of the norbornene comonomer. The other major variable, molecular weight, determines

the rheological properties.

The family of COC resins is fully amorphous and shares many common features. The

exceptional purity and absence of chromophores in COC resins makes them both glass clear and

water white. Mechanically, these materials are strong, stiff and brittle, very much like PVC or

PS.

COC in Flexible Films

COCs can be used in two ways in packaging films: as an individual layer of COC (mono

COC) or multilayer structure. With a multilayer, the moisture barrier will be the highest. The

COC layer will contribute significantly to film stiffness. In the case of very thick COC layers, the

films can be thermoformed for pharmaceutical blister packs. A second, and possibly more widely

applicable way to use COCs in packaging would be as a blend in polyolefins to accomplish

specific modification of the film. COCs alter the characteristics of polyolefin films in many

ways. They increase the modulus, maintain or lower the haze, reduce the COF and blocking

tendency, improve sealing behavior and improve the MVTR for the polyolefin. Any one of these

improvements may not be enough to justify its use; but taken in total, these benefits allow for

innovative design of film structures. The increased modulus of the blends can allow for down

gauging of the film at equivalent stiffness; or create a stiffer film at the original film gauge; or an

intermediate combination, which will satisfy the design and economic constraints.

16

COC also improves the hot tack strength. The absolute value of the hot tack force is

increased significantly, and the peak force is extended over a wider temperature range than the

base resin. This can translate to faster packaging line speeds and less delamination since the

package seals are stronger at higher temperatures. As mentioned earlier. While polyolefins are

not considered to be good moisture barriers, COCs have excellent moisture barrier. COCs can

improve theMVTR of these materials. This can influence the shelf life of moisture sensitive

products.

There are many factors to be considered in the design of flexible packaging films. Among

these are the appearance of the film, what is to be packaged, film properties desired, package

economics, and esthetics. In the case ofmultiplayer films, the properties are a blend of the

properties of the individual layers and how they are arranged.

Environmentally Safe Blister Packaging with ImprovedBarrier Properties

The packaging of medicines has to meet particularly demanding criteria. These include

bio-compatibility, reliable protection against external influences, optimum shelf life, clear

identification, and easy of handling and dispensing. For medicines in tablet form, blister packs

have become the standard. They not only meet all technical conditions required by

pharmaceutical companies, but they are also easy and safe for use by patients. A safe,easy-to-

use package promotes the patient's compliance to directed dosage, a crucial factor for successful

treatment. Each individual tablet is clearly visible and can easily be pushed through the

aluminum foil. A key component is the plastic film, which, in combination with the aluminum

foil that forms the base, covers the tablets at the top in a blister pack. The plastic film must have

the highest possible transparency and simultaneously provide protection against moisture and

(for sensitive products) oxygen. The combination of high moisture barrier, clarity, and

thermoformability supports use of COC in pharmaceutical blister and personal care packaging.

17

When blended with polyolefins, COC dramatically increases stiffness allowing down gauging of

films (Capus, 2001).

Processing

COC can be compounded with pigments, lubricants, glass fibers, flame-retardants and

other additives and fillers. It can be processed by a range ofmethods, including injection

molding; film, sheet and profile extrusion; and injection blow molding. Drying and other special

pretreatments are not needed. Extruded COC films can be biaxially stretched for use in

capacitors, monoaxially stretched for shrink-wrap applications, or used as is in laminates. Biaxial

orientation greatly improves film mechanical properties. COC can be coextruded with low

density PE without a tie layer, but with other resins, such as PP, polyester, nylon, ethylene vinyl

alcohol or PC, a tie layer is generally required for good adhesion.

Properties ofCOC (Provided by Ticona a division of Celanese, Summit, New Jersey )

Density 1.02 g/cc

Water absorption <0.01 %

Water vapor permeability @ 85%RH 0.02-0.04 g/m2/ day

Tensile strength 9,570 psi

Elongation @ break 3-10 %

Tensile modulus 377-464 kpsi

Flexural modulus 0.5 Mpsi

Modulus of elasticity, Tg > 100C 3,100-3,300 Mpa

Charpy impact 13-20kJ/m2

Notched charpy impact 1.7-2.6kJ/m2

Hardness 89 Shore D

Glass transition temperature 70-180 C

Heat deflection temperature @ 66 psi 75-170 C

Melt Flow Index at 260C 12-55 g/10 min.

Dielectric constant @ 60 Hz 2.35

18

Dielectric loss @ 60 Hz <0.02 %

Dielectric breakdown 30 KV/mm

Comparative tracking index >600 volts

Volume resistivity >10 16 ohm-cm

Light transmission 92 %

Refractive index 1.533

Pharmaceutical Blister Packaging Requirements

Pharmaceutical packaging constitutes an interesting growth market for COC because it

has to meet a diversity of requirements. It must protect the contents; it must be easy to handle

and open; it must be tamper-proof; and it must provide the patient with all necessary information.

Blister packs have proved ideal for pharmaceutical products in tablet form. The combination of a

transparent plastic film with an aluminum foil renders each individual tablet visible. The user can

remove the tablet simply by pressing it through the foil. The other tablets remain well protected

until it is their turn to be taken. Moreover, its manufacture is less costly than the process of

sealing tablets between two layers of aluminum foil. Extreme demands are made on the plastic

film or, to be more precise, on its barrier effect against moisture vapor transmission rate

(MVTR) when the blister pack is to be used in tropical regions, that is to say, in regions where

high temperatures and a high relative humidity prevail. In such cases, the blister pack must meet

the following requirements:

It must reliably protect the tablets, which often contain hydroscopic sensitive

compounds, against moisture for a period of at least two years.

It must be tamper proof, both in respect to the packaging as a whole and the

packaging of each individual tablet, thus guaranteeingthe genuineness of the

contents.

It must be possible to sell the tablets individually.

It must afford a high degree of protection against counterfeiting (product piracy).

19

In order to improve the functional properties of blister packs, the COC film is coated on

both sides with a thin layer of polypropylene. These layers not only improve the tensile impact

strength of the relatively brittle COC film, but also add high grease resistance to its existing

water vapor impermeability. Moreover, the packaging industry has already had many years of

practical experience with polypropylene as a packaging material with direct contact with

pharmaceuticals products, making any further large scale, time-consuming trials unnecessary.

The water vapor impermeability increases in direct relation to the increase in the thickness of the

COC layer.

TEST RESULTS

Research was conducted to compare olefin structures (such as PP/COC/PP) to halogen

based material (e.g., PVC/PVDC) that corrode equipment and/or form toxic hydrofluoric and

hydrochloric acids. The following standard COC film structures were used in the testing:

COC Coex Film 120 micron - 20 micron PP / 45 micron PE tie layer / 120 micron

COC / 45 micron PE tie layer / 20 micron PP (total thickness 250 micron).







These COC structures were tested against

These COC films were compared to a control package of PVC coated PVDC with the following

properties: Klockner PVC/PVDC Barrier film 200/25/40 (200 micron PVC, 25 micron PE,

coated with 40 g/m2 PVDC (total thickness 200 micron). The COC and PVC films were

compared based on the following criteria:

20

MVTR - to determine the moisture permeation of a unit dose blister using test

method - United States Pharmacopeia USP25 <671> titled "Single-Unit Containers

and Unit-Dose Containers For Capsules and Tablets"(United States Pharmacopeia

Convention, Inc., 2001).

Vacuum Leak Test

Peel strength test

Layer distribution

Machine-ability and form-ability

Price comparison based on surface area

The results of the study, and a discussion of how COCs can be utilized effectively in the

design of flexible films, is described below.

MVTR

On an Uhlmann thermoformer (Model # UPS4 MT - see Figure 1) line at the Pfizer plant

in Parsippany, NJ, approximately 10,000 blisters of each of the following structures were

formed.









Klockner PVC/PVDC Barrier film 200/25/40 (25 micron PVC coated with 40 g/m2

PVDC (total thickness 200 micron).

21

Figure 1. Uhlmann Thermoformer, Model # UPS4 MT (Pfizer Parsippany Plant).

22

The tooling that was used to form all of the test sets is the same tooling that is used for

the production of Zyrtec (single dose). The tooling is a 9 up design (3x3 configuration). To

minimize variability in the test method I held certain equipment settings as constant as I was able

i.e. the speed and sealing temperature were not varied as long as I had was able to achieve a good

sealed blisters. The criteria for a good blister is that it would pass the leak test, the appearance of

the cavity is well defined and the foil backing is within the specification. The upper and lower

preheat temperatures were modified slightly to achieve a fully formed cavity. The machine

settings are summarized in Table 1.

Table 1. Packaging Thermoformer Equipment Setting.

Equipment Settings COC 120 COC 190 COC 240 COC 300 PVC/PVDC

Forming Preheat Upper

Temperature (degrees Celsius)

110/115/120 110/115/120 110/115/125 110/115/125 110/115/120

Forming Preheat Lower

Temperature (degrees Celsius)

110/115/120 110/115/120 110/115/125 110/115/125 110/115/120

Sealing Temperature (degrees

Celsius)

185 185 185 185 185

Machine Speed (cycles per

minute/blisters per minute)

40/360 40/360 40/360 40/360 40 / 360

Nine (9) samples representing one stroke (cycle) from each film configuration were filled

with 75 mg desiccant and marked appropriately. Samples were placed in an Environmental

Chamber (Model* Canon 6030 Unit #4 SN# 042503-6656-04) set at 23 degrees C with 75%

humidity. The environmental chamber was calibrated on 03-12-04; the next due date for

calibration is 09-12-04. Samples were weighed at 0 days, 1 day, 2 days, 3 days, 8 days, and 36

days. The weights were measured on an electronic balance (Model # Mettler Toledo AE163

serial number F30461) whose balance was calibrated on 03-04-2004; the next calibration is due

sometime in September 2004. The results were recorded (see Tables 2-7 and Figure 2 on the

following pages) and a report summarizing the results was approved.

23

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Table 7. MVTR Data Summary.

Rate ofMoisture Permeation (mg/day)

COC 120 COC 190 COC 240 COC 300 PVC/PVDC

Time Elapsed Max Min Max Min Max Min Max Min Max Min

24 hours (day 2 - day 1) 0.800 0.200 0.600 0.200 0.200 -0.200 0.100 -0.200 -0.300 -0.800

48 hours (day 3 - day 1) 0.300 0.050 -0.100 -0.200 -0.100 -0.250 -0.050 -0.150 -0.050 -0.200

7 days (day 8 - day 1) 0.043 -0.043 0.114 0.029 0.157 0.100 -0.014 -0.043 -0.014 -0.071

28 days (day 36 - day 8) 0.071 0.046 0.033 0.014 0.004 -0.014 0.061 0.043 0.079 0.061

According to the USP 25 test method <671> all of the samples meet class"A"

specification

since none of the samples exceeded the 0.500 mg/day at the 28 days test.

-0.02

Rate ofMoisture Permeation (mg/day)

Film

? COC 120 Max

COC 120 Min

? COC 190 Max

? COC 190 Min

COC 240 Max

B COC 240 Min

COC 300 Max

? COC 300 Min

PVC/PVDC Max

PVC/PVDC Min

Figure 2. MVTR Data Graph.

Note-COC 240 minimum daily permeation ended up

in the negative region (-0.014 mg/day) is

due to the measurement of a very narrowrange with an analytical scale of 0.010 milligram

statistical noise.

29

Vacuum Leak Test

A Vacuum Leak Test was completed on 9 blisters randomly picked from the 10,000

blisters for each film configuration. The Vacuum Leak Tester that was used (Model # ATS Item

# 1 109 -

see Figure 3) was last calibrated on 4-30-2004; the next calibration is due July 2004. A

digital stopwatch was also used; it was last calibrated on 4-13-2004 with its next calibration due

April 2005.

Figure 3. Blister Vacuum Leak Tester (Pfizer Parsippany Plant).

The vacuum chamber was filled with water and a red dye solution which contained FD+C

red 40 CAS 25956-17-6. The product was placed inside the chamber and a weight was placed on

the samples to keep them submersed. The weight contained holes to keep the vacuum pressure.

The vacuum pump was turned on until thevacuum pressure reached 15 PSI. After a 60 second

wait, the vacuum pump was turned off andthen opened once it reached equilibrium pressure.

The product was then removed from the vacuum chamber and rinsed in clear water, and the

30

samples tapped dry. The sample cavities were then checked for the red liquid. The results are

recorded in Table 8 below.

Table 8. Vacuum Leak Summary.

Vacuum Leak Test


Blister #1 Pass Pass Pass Pass Pass









Peal Strength Test

A Chatillon Peal Test Machine (Model # LTCM-5 Serial # 13377 - see Figure 4), last

calibrated on 08-14-2003 and due to be recalibrated in August 2004, was used to test the bonding

of the film to the foil.

Figure 4. Blister Peal Strength Tester (Pfizer ParsippanyPlant).

31

IT-1125 was the test protocol used to test the blisters listed in Table 9. Results of the test are

shown in Figure 5.

Table 9. Peal Strength Summary.

Peal Strength Test (lbs.)

COC 120 COC 190 COC 240 COC 300PVC/PVDC

(control)Blister #1 3.41 6.42 5.52 6.43 1.64

Blister #2 4.04 5.13 5.39 5.48 3.56

Blister #3 5.60 6.05 5.34 5.94 1.61

Blister #4 5.18 5.71 4.95 6.36 0.46

Blister #5 11.10 5.54 5.49 6.02 4.82

Blister #6 5.86 5.72 5.87 8.02 1.36

Blister #7 7.71 6.20 5.74 5.83 2.80

Blister #8 7.55 5.81 6.71 7.43 5.24

Blister #9 5.19 5.84 5.90 8.16 6.22

Average 6.18 5.82 5.66 6.63 3.08

?Percent

ofControl201% 189% 184% 215% N/A

* Percent ofcontrol= the COC average peal strength divided by the average control peal

strength (PVC/PVDC)

Peal Strength Test

COC 120

? COC 190

COC 240

COC 300

H PVC/PVDC


Figure 5. Peal Strength Graph.

32

Optical Layer Gauge

A Davinor Layer Gauge (Model # IID Multilayer Thickness Gauging, Serial No. #109

rr-1 125) was used to test the distribution of the different layers within the cavity. Davinor Inc.

calibrates the instrument annually.

Detector signal

Figure 6. The Davinor Layer Gauge (Davinor, 2004).

The Davinor Layer Gauge instrument (see Figure 6) is designed to measure thickness of

the individual layers ofmultilayer materials. Its main targets of application are transparent and

semi transparent multilayer plastic films. On the basis of its structure, the Layer Gauge is

suitable for a measuring of especially thin film materials (Davinor, 2004). The testing results are

shown in Table 10 and Figure 7 that follow.

33

Table 10. Optical Layer Gage Summary.

COC 12C) COC 190

Preformed Film Preformed Film

Measurement (micron) PP COC PP Measurement (micron) PP COC PP

1 65.9 126.5 67.2 1 36.4 208 37.7

2 67.9 127.8 67.8 2 36.4 208 36.9

3 67.4 126.5 65.8 3 36.9 208 36.7

Average 67.1 126.9 66.9 Average 36.6 208.0 37.1

Blister 1 Blister 1


Side 33.8 63.5 31.9 Side 23 121.7 21

Top 43.9 87.5 43.4 Top 25.9 126 23.9

Blister 2 Blister 2


Side 39.6 76.2 40.6 Side 22.7 126.7 26

Top 43.9 84.7 44.7 Top 27.3 136 25.4

Blister 3 Blister 3


Side 33.3 83.3 33.1 Side 19.4 98.9 19.5

Top 44.6 85.3 44.9 Top 23.7 132 25.4

Top Average 44.1 85.8 44.3 Top Average 25.6 131.3 24.9

Side Average 35.6 74.3 35.2 Side Average 21.7 115.8 22.16667

COC 24() COC 300

Preformed Film Preformed Film


1 35.8 254.9 37.8 1 40 307 43.5

2 34.4 253.5 36.3 2 42.8 305.6 42.1

3 34.4 254.5 36.3 3 41.4 308.4 43.6

Average 34.9 254.3 36.8 Average 41.4 307 43.1

Blister 1 Blister 1


Side 20.5 121.4 18.5 Side 18.9 165.6 20.2

Top 25.9 153.8 23.2 Top 21.6 189.8 24.7

Blister 2 Blister 2


Side 18.7 113.9 17.4 Side 15.2 190.4 24.6

Top 28.8 160.9 29 Top 17.3 211 29.1

Blister 3 Blister 3


Side 24.4 126.5 23.2

29

Side 15.8 184.3 20.2

Top 28.8 159.4 Top 20 200 26.1

Top Average 27.8 158.0 27.1 Top Average 19.6 200.3 26.6

Side Average 21.2 120.6 19.7 Side Average 16.6 180.1 21.66667

(Tab e continues)

34

Table 10 (continued)

PVDC-PE-PVC

Preformed Film

Measurement PVDC PE PVC

1 22.4282 34.3154 205.5368

2 21.7678 34.3154 204.089

3 22.4282 33.9852 203.0476

Average 22.208 34.205 204.224

Measurement

Side

Top

PVDC

9.525

9.525

Blister 1

PE

15.7226

17.8308

PVC

103.9876

15.7226

Blister 2


Side 12.192 19.9898 116.459

Top 11.5824 18.5166 116.5606

Blister 3


Side 11.0998 18.0086 118.2878

Top 10.8712 20.701 115.189

Top Average 10.660 19.016 82.491

Side Average 10.939 17.907 112.911

Summary ofMaterial Distribution


Preformed 260.9 281.7 326 391.5 260.4

Top 174.3 181.9 212.9 246.5 112.2

Side 145.1 159.6 161.5 218.4 141.8

Top as a % ofpreformed 67% 65% 65% 63% 43%

Side as a % of preformed 56% 57% 50% 56% 54%

35

Material Distribution

? Preformed

Top

DSide

COC 120 COC 190 COC 240 COC 300 PVDC/PVC

80%

70%

60%

50%

40%

30%

20%

10%

0%

Material Distribution

? Top as a % of preformed

Side as a % of preformed

COC 120 COC 190 COC 240 COC 300 PVDC/PVC

Figure 7. Material Distribution Graph.

36

Price Comparison

Converters of the COC and PVC/PVDC materials generated the prices. All prices were

based on 20,000 kg annual volume. Results are shown in Table 11 and Figure 8 below.

Table 11. Price Comparison.

$/kg $/lbs $/1000 square inches

COC 120 $9.24 $4.20 $1.41

COC 190 $9.46 $4.30 $1.60

COC 240 $10.12 $4.60 $1.99

COC 300 $10.45 $4.75r

$2.43

PVC/PVDC $4.38 $1.99 $1.31

Price Comparison

G

,0

<P 5>fS>

G

.0

\

0

.0

V

G

,0

<*

A'o

A9,0

Figure 8. Price Comparison Graph.

The COC family yields more area per kg,which makes the material somewhat competitive in

pricing to the PVC/PVDC or Aclar family.

37

CONCLUSION

The following is a summary of the test results:

TheMVTR for the COC family is slightly better than that of PVC/PVDC and both

meet the USP class"A"

designation.

The vacuum leak test passed for all of the material.

The Peel strength test on an average was twice as good for the COC than that of

PVC/PVDC.

The material distribution is also better for the COC family that that of PVC/PVDC.

The machine-ability and form-ability was the same for both; the equipment produced

10,000 blisters at a rate of 40 cycles/minute or 360 blisters/minute. However,

excessive static build up was noticed during the die cutting of the COC. This could

present frequent stoppages if the static is not alleviated. There are a few different

methods currently available that reduce or even eliminate static build up, such as

static bars, ionized air, grounding of the die cutting tool, etc. Also, all of the PVC

based families corrode the tooling, which requires frequent and costly repair or the

purchase of a new tool. COC is an Olefin material, which does not affect the tooling

in any form.

The price of COC is equally competitive to the COC 120 and slightly higher to the

COC 190, but 52% and 85% higher than COC 240 and COC 300, respectively.

However, once COC is accepted by the pharmaceutical industry and production

volume increase, it is predicted that the price will come down to competewith other

materials. Based on the potential health hazard of PVC and its family ofmaterials, the

cost ofmedical claims and litigation could single handedly justify the conversion to a

more friendly structure.

Based on these results, it was concluded thatCyclic Olefin copolymers provide new tools

for the design of flexible packaging in thepharmaceutical industry and beyond. COCs can

38

improve many of the properties of polyolefins. Among these are modulus, clarity, blocking,

sealing, andMVTR. Because of the enhancement in modulus, COCs offer significant

downsizing possibilities. Above all COC will not contribute to the destruction of the

environment while it enhances the company's image as leader that has emerged from the PVC

market. COC is an Olefin not like PVC it does not corrode the tooling, which would yield to

significant saving in constant tooling refinishing or replacement.

CONSIDERATIONS

Modification to the thermoformer to include static bars, ionized air, and/or grounding

devices to minimize static at the die cutting station might be required.

The PVC pricing is systematically coming down, which makes it difficult to justify

the project with no direct return on investment.

Changing from the current approved material would require new stability studies and

new submission to the FDA.

Currently, COC resin is only produced in one factory (Germany). If for any

unforeseen reason the production is disrupted, this could drastically affect the

production of the end user, which would in turn contribute toloss of market share.

39

REFERENCES

About. (2004). Wallace Hume Carothers. Retrieved July 13, 2004 from http://inventors.about.com/

Capus, J. M. (2001). Advancedmaterials andprocesses. AM&P, 159, 25.

CMS Info. (2004). Retrieved July 13, 2004 from http://www.biz-lib.com/info/6479.pdf

Clayton, H. (1991). Environmental Consultant, Norsk Hydro at 12th Plastics Seminar, Portugal,November 1991.

Committee on Medical and Biologic Effects of Environmental Pollutants. (1976). Chlorine and

hydrogen chloride. Washington, D.C.: Washington National Academy of Sciences.

Davinor, Inc. (2004). Technical description ofDavinorLayerGauge measuring system. Retrieved

July 13, 2004 from http://www.davinor.com/Products/layergauge technical.htm

Draguta, V., Balaban, M., & Dimonie, AT. (1985). Olefin metathesis and ring-opening

polymerization ofcyclo-olefins(2nd

edition). New York: Wiley.

Encyclopedia Britannica (2004). Hermann Staudinger. Retrieved July 13, 2004, from Encyclopaedia

Britannica Online.

Environment Safety and Health Manual. (2004). Retrieved July 13, 2004 from

http://www.llnl.gov/es and h/hsm/doc 14.14/docl4-14.html

Finlayson, K. M. (Ed.). (1993). Plasticfilm technology (Vol. 1). Lancaster, PA: Technomic Publishing

Company Inc.

Greenpeace Austria. (1991) PVC: Toxic Waste in Disguise. Retrieved July 13, 2004 from

http://www.mindfully.org/Plastic/PVC-Disguise-Greenpeacel992.htm

H. S. Eleuterio, US Pat. 3074918; filed 20 June 1957, patented 22 January 1963; Chemical

Abstract 55,16005 (1961).

Imamolgu, Y., Zumreoglu-Karan, B., Amass, A.J. (Eds.). (1990). Olefin metathesis and polymerization

catalysts, synthesis, mechanism, andutilization. Dordrecht, Boston, London: published in

cooperation

with the NATO Scientific Affairs Division.

Ivin, K.J. andMol, J.C. (1997). Olefinmetathesis andmetathesis

molymerization. San Diego:

Academic Press.

Marshall, S. (1968). Olefins manufacture andderivatives. Park Ridge, N.J.: Noyes Development

Corp.

Mindbranch.com. (2004). PharmaceuticalPackaging. RetrievedJul)'13, 2004 from

http://www.mindbranch.com/aitaj^^

40

Ozone Depletion Glossary. (2004). Retrieved July 13, 2004 from http://www.epa.gov/ozone/defns.html

PBS.org. (2004) Trade Secrets Confidential: A Moyers Report. Retrieved July 13, 2004 from

http://www.pbs.Org/tradesecrets/problem/problem.html#

Selke, S. E. M. (1990). Packaging and the environment. Lancaster, PA: Technomic Publishing

Company, Inc.

Seymour, R. B. (Ed.). (1982). History ofpolymer science and technology. New York: M.

Dekker.

Titow,W.V. (1984). PVC technology(4th

edition). New York: Elsevier Applied Sciences.

UK Health and Safety Executive. (1975) Vinyl Chloride-Code ofPracticefor Health

Precautions. February 1975.

United States Pharmacopeia Convention, Inc. (2001). The United States Pharmacopeia <USP

25>. Toronto: Webcom Limited.

41

APPENDIX A: DEFINITIONS

Amorphous: Having no ordered arrangement. Polymers are amorphous when their chains are

tangled up in no specific arrangement. Polymers are not amorphous when their chains are lined

up in orderedcrystals.

Copolymer: A polymer made from more than one kind of monomer.

Crystal: A mass of molecules arranged in a neat and orderly fashion. In polymer crystal the

chains are lined up neatly. They are also bound together tightly by secondary interactions.

Glass transition temperature: The temperature at which a polymer changes from hard and

brittle to soft and pliable.

Hydrogen bond: A very strong attraction between a hydrogen atom which is attached to an

electronegative atom, and an electronegative atom which is usually on another molecule.For

example, the hydrogen atoms on one water molecule are very stronglyattracted to the oxygen

atoms on another water molecule.

8",H

8+0-

\ The hydrogenwith a partial positive

/

^charge is attracted to the oxygen with

0^ its partial negative charge.

H

Modulus: The ability of a sampleof a material to resist deformation. Modulus is usually

expressed as the ratio of stress exerted on thesample to the amount of deformation. For example,

tensile modulus is the ration of stress applied to the elongation,which results from the stress.

Monomer: A small molecule which may react chemicallyto link together with other molecules

of the same type to form a large molecule called apolymer.

OlefinMetathesis: A reaction between two molecules,both containing

carbon-carbon double

bonds. In olefin metathesis, the double bondcarbon atoms change partners,

to create two new

molecules, both containingcarbon-carbon double bonds.

RR'

>=<R

R'

R R R\R'

V../

A Ar: r

r* R"

r

RR"

42

Plasticizer: A small molecule that is added to polymer to lower its glass transition temperature.

Ring-opening polymerization: A polymerization in which cyclic monomer is converted into a

polymer, which does not contain rings. The monomer rings are opened up and stretched out inthe polymer chain, like this:

AB'

AAAAM j!^s

XB A>^J} MWNB A^

Strength: The amount of stress an object can receive before it breaks.

Thermoplastic: A material that can be molded and shaped when it's heated.

Thermal decomposition: A change that takes place in a material when you heat it or cool it,

such as melting, crystallization, or the glass transition.

Thermoset: A hard and stiff crosslinked material. Thermosets are different from thermoplastics,

which become moldable when heated. Thermosets are crosslinked, so they don't. Also, they are

different from crosslinked elastomers. Thermosets are stiff and don't stretch the way elastomers

do.

43

Documents

Cyclic Olefin Copolymer (COC) in the pharmaceutical industry